There is considerable evidence to support the theory that some form of renal dysfunction plays a role in the development and maintenance of hypertension. In several forms of genetic hypertension, a common defect has been identified in the pressure natriuresis relationship. The defect in hypertensive animals is partly due to an inability to transmit renal perfusion pressure into the renal interstitium. The goal of this proposal is to examine possible mechanism that mediate this intrarenal abnormality. In recent studies, endothelin (ET) and nitric oxide (NO) have been shown to have significant effects on renal excretory function and that synthesis of these factors may be altered in hypertension. The main objective of this proposal is to test the hypothesis that the inability to transmit the renal perfusion pressure into the renal interstitium is due to abnormalities in the renal autocoids such as NO and ET. A variety of techniques including microcirculatory, whole kidney, and whole animal will be used to examine the roles of ET and NO in contributing to the abnormal pressure natriuresis in different models of hypertension. The questions that will be addressed are: 1) Is the inability to transmit renal perfusion pressure into the renal interstitium in Dahl S rats due to a decrease in NO synthesis? 2) By what mechanism does L-arginine restore the normal pressure natriuresis relationship in Dahl S rats? Does L-arginine improve transmission of RPP into the renal interstitium by affecting medullary hemodynamics? 3) Does chronic renal interstitial infusion of a NO synthase inhibitor into Dahl R rats render them salt- sensitive? 4) What role does ET play in the abnormal pressure natriuresis in various forms of hypertension? Does infusion of an ET receptor antagonist improve the transmission of RPP into the renal interstitium? 5) What role does ET lay in the progression of hypertension: Does chronic infusion of an ET receptor antagonist lead to long-term reductions in arterial pressure in various forms of hypertension?